The von HippeI-Lindau (VHL) syndrome is a hereditary disease that is characterized by the development of highly vascularized tumors. Its underlying genetic defect is in the VHL tumor suppressor gene. The VHL mutant therefore represents an excellent system for studying the tumor-induced angiogenesis. We have identified an evolutionarily conserved novel mutational mechanism that leads to FGF receptor (FGFR) over-accumulation on the cell surface in VHL mutants. This phenomenon is observed in Drosophila, in the malignant renal cell carcinoma (RCC) culture, and likely in the human microvascular endothelial cells (HMVECs). It was also noted that the over-accumulated FGFR leads to aberrant cell migration and induction of Ets1 activity, whose function has been linked to metastasis and angiogenesis. We have previously found that the function of VHL is likely mediated by another tumor suppressor gene nm23. Based on these preliminary data, a novel intracellular mechanism is proposed that underlies the FGFR accumulation phenotype in VHL and nm23 mutations (as in human VHL disease patients and in Drosophila developmental mutant) and how this aberrant signaling event, via Ets1, can modulate cell motility during angiogenesis. We will utilize in vitro and in vivo model systems and employ cross-species comparative studies to dissect the signaling mechanisms. Aim 1 will dissect the vesicle transport pathway that results in FGFR over-accumulation. Aim 2 will analyze the role of VHL, FGFR, and Ets1 in modulating angiogenesis, employing a 3-dimensional co-culture system. Aim 3 will examine the novel function of VHL in relation to Nm23. Aim 4 will employ knockout mice to test the hypothesis that VHL heterozygous mutation in endothelial cells in the VHL disease patients play an important role in the disease' highly vascularized tumorigenic characteristics.